Correction: An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies.

ISSN:1420-682XISSN:1420-907

An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies.

PURPOSE Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells. EXPERIMENTAL DESIGN: We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment. RESULTS We identified an 'oncogene addiction phosphorylation signature' (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments. CONCLUSIONS We propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene

Méthodologie globale de gestion des risques : De la gestion de crise à la continuité d’activités, entre élaboration des procédures et mises en situations

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Fetal cells for intervertebral disc regeneration

Degeneration of the intervertebral disc (IVD) is thought to be one main factor in the development of back pain. It is not a symptom by itself but can lead to painful pathological conditions. Current treatments aim at relieving pain by conservative care, medications or surgical removal of the painful part of the disc but do not treat the causes. Disc degeneration is a progressive process which begins in the center of the disc by the loss of water due to impaired cell activity. Our hypothesis is that regeneration of the disc at the first stages of degeneration is likely to delay the progression and the need for surgery. Regeneration could be achieved by a cell-based therapy, which would bring active matrix producing and/or growth factor delivering cells. The up-scaling from bench-side to clinic for a cell therapy is limited due to safety and consistency matters. Thus, the choice of cell-type is of utmost importance to assure consistent efficacy and safety of a therapeutic application. The aim of this work was to characterize human fetal cells isolated from fetal cartilaginous tissues regarding their potential for the correction of IVD degeneration. In a first step and first chapter, a methodology for creating consistent and safe fetal cell banks from only one single tissue donation was developed. This method was illustrated by the example of fetal skin cells, which dedicated cell banks have already been tested in clinical trials. Secondly, in the second chapter, the isolation and chondrogenic potential of fetal spine cells was presented. Fetal cells were isolated from spine units (2 IVDs and 1 vertebra) from 5 donors aged from 12 to 16 weeks of gestation and amplified in monolayer to establish dedicated and consistent cell banks. Alginate bead cultures of fetal spine cells showed heterogenous matrix synthesis ability. Two fetal cell donors (14 and 15 weeks of gestation), showed good aggrecan and type II collagen production with very low type X collagen production. Mesenchymal stem cells (MSCs) can be differentiated into several phenotypes and show good regeneration capacity. Fetal cells also show good regeneration property but there is little information concerning their plasticity. Thus, in chapter three, the plasticity of fetal spine cells was investigated and compared it to that of MSCs. Cells isolated from fetal articular cartilage were also investigated as they also represent a potential source of fetal cartilaginous cells. Similarly to MSCs, fetal cells from both origins were positive for surface markers CD44, CD73, CD105 and CD166 and were negative for CD34 and CD45. Fetal cells exhibited much lower adipogenic and osteogenic differentiation levels than MSCs. As expected, fetal cells showed high chondrogenic differentiation, showed by aggrecan and type II collagen production, in TGF-β3 stimulated high cell mass density system. A mild level of type X collagen was detected in fetal spine cell pellets, whereas fetal cartilage cell pellets were highly positive. In chapter four, the response of fetal spine cells to glucose deficiency and hypoxia was assessed since these stress conditions would be similar to those of the in vivo disc. Viability of fetal cells cultured in monolayer was not altered by glucose level in normoxia and under 5% oxygen but was decreased by low glucose levels under 2.2% oxygen. Hypoxia induced an increase in SOX-9 gene expression independently of glucose level. However, a trend for a decreased gene expression of aggrecan and type I collagen under hypoxia and deficiency in glucose was observed. Finally in chapter five, fetal spine cell conditioned media (FSCCM) was tested for anti-inflammatory properties in a model of interleukin-1 (Il-1) stimulated nucleus pulposus (NP) cells. Il-1 stimulated bovine NP cells showed decreased cycloxygenase-2 (COX-2) expression and increased Prostaglandin E2 (PGE2) production in response to FSCCM, whereas human NP cells showed a decreased COX-2 gene expression as well as decreased PGE2 production. Molecular weight fractions of FSCCM had the same inhibitory effect than whole FSCCM, indicating that activity of FSCCM is more likely due to a combination of compounds rather than to a single molecule. In conclusion, fetal spine cells have been shown to be a good candidate for IVD regeneration. Fetal cell banks can easily be established and provide consistent cell lots with the extensive safety testing accomplished to assure necessary security for the patient. However, donor to donor variation in the matrix synthesis capacity will impose a strict donor selection, which could be based on spontaneous matrix synthesis in alginate bead culture. Type X collagen production was very low in unstimulated cells but could be induced by chondrogenic factors, indicating a potential risk for endochondral ossification, risk which should be assessed in an in vivo model. On the other hand, the ability of fetal spine cells to survive in low oxygen and glucose conditions, their low plasticity and their anti-inflammatory properties are interesting advantages for IVD regeneration

Identification des différences de traitement des évènements internes, agressions internes et agressions naturelles extrêmes, lors de l’évaluation du risque d’une installation industrielle.

International audienceCet article présente les travaux effectués dans le cadre du projet IMdR P18-1 (souscrit par EDF, INERIS, IRSN, TOTAL), qui vise à améliorer l'évaluation de risques, dans le cas où des installations industrielles ou nucléaires peuvent se trouver menacées par des agressions naturelles extrêmes. L'objectif final est de permettre aux industriels de poursuivre l'inter-comparaison de leurs pratiques et de leur proposer un formalisme de traitement cohérent et de portée générale des évènements internes et agressions internes ou agressions externes ainsi que des éléments pouvant contribuer à arbitrer des actions d'amélioration possibles de leurs systèmes

Power converter design for HVDC applications

This thesis investigates the design of modular voltage source converters for High Voltage Direct Current (HVDC) applications. The first half of the thesis focuses on the design of existing multilevel HVDC technology. A design methodology for sizing modular converters for a given grid code specification, and with given design constraints in terms of peak sub-module voltage rating and capacitor size, is developed and used as the basis of comparing converter designs. Results show that the half-bridge MMC requires an energy storage in the region of 35 kJ/MVA in order to achieve a good balance between sub-module capacitor size, and required number of sub-modules. The design of the Hybrid MMC, which combines half- and full-bridge sub-modules in the design in order to achieve DC fault tolerance, is then investigated using the same design methodology, an advantage of which is that the optimum modulation index can be determined, rather than assumed. Results show that the highest efficiencies may be achievable if the converter is operated at a modulation index of 1.2. The power-loss and thermal properties of several converters are then analysed. The Alternate Arm Converter and over-modulating Hybrid MMC show the greatest efficiencies, though the AAC suffers from relatively high junction temperatures within its director switches. The potential of designing overload capability into MMCs, to enable them to provide system support services such as frequency response is then investigated. Results show 30% overload ratings may be achievable with only a 10% require increase in the number of sub-modules within the converter. System studies show that significant response improvements to the AC system can be made even if the converters need to be dynamically rated to prevent excessive junction temperatures being reached. The second half of this thesis focuses on a brand new multilevel thyristor-augmented structure called a power-group, which has the potential to allow voltage source converters that are tolerant to faults on both the AC and DC network to be constructed, while having efficiencies similar to those achievable with Current Source Converter (CSC) technology. Results show that this is possible while also retaining high quality current waveforms and independent control of real and reactive power. Results throughout the thesis are backed up by a combination of simulation and experimental work using a lab-scale multilevel converter that was constructed during the project.Open Acces

Monitoring Tantalum nitride thin films structure by reactive HiPIMS magnetron sputtering : from microstructure to properties

International audienc

Monitoring Tantalum nitride thin films structure by reactive HiPIMS magnetron sputtering : from microstructure to properties

International audienc